Abstract
Cancer is the most challenging disease of our time with increasing numbers of new cases each year, worldwide. Great achievements have been reached in cancer research through deep sequencing which helped define druggable targets. However, the still-evolving targeted therapy suffers resistance suggesting that DNA mutations considered as drivers may not have a role in tumor initiation. The present work discusses the role of DNA mutations as drivers and passengers in cancer initiation and development. First, it is important to discern the role of these DNA mutations as initiating events causing cancer or as contributors crucial for the development of a tumor once it has initiated. Second, breast cancer shown here illustrates how identification of DNA mutations in cancerous cells has influenced our approach for anti-cancer drug design. The cancer trilogy we have reached and described as: initial drug; resistance/recurrence; drug/treatment combinations, calls for a paradigm shift. To design more effective cancer drugs with durable and positive outcome, future cancer research needs to move beyond the sequencing era and explore changes which are taking place in cancer cells at levels other than the DNA. Evolutionary constraints may be acting as a barrier to preserve the human species from being transformed and, for that matter, all multi-cellular species which can incur cancer. Furthermore, mutations in the DNA do occur and for a multitude of reasons but without necessarily causing cancer. New directions will draw themselves when more focus is given to the event responsible for the switch of a cell from normalcy to malignancy. Until then, targeted therapy will certainly continue to improve the outcome of patients; however, it is unlikely to eradicate breast cancer depicted here.